Stem cell therapy is a putative treatment for end-stage heart failure. Bone marrow-derived mesenchymal stem cells (MSC) improve cardiac function following intramyocardial transplantation. Our previous study indicates that MSC preprogrammed to express GATA-4 (MSCGATA-4), a well-known cardiac transcription factor, significantly accelerate ischemic heart repair - by increasing MSC survival and differentiation, as well as angiogenesis. However, the mechanism is unclear. The recently discovered endogenous class of small non-coding RNAs, microRNAs (miRs), plays an important role in both cardiac protection and pathology associated with myocardial ischemia. Our preliminary data indicate that overexpression of GATA-4 in MSC modulates expression of several miRs which can then transfer from MSC into neighboring cardiomyocytes (CM). We propose the following two hypotheses: Hypothesis 1: Specific miRs and miR targeted genes mediate potent pro-survival and pro-angiogenic effects. Hypothesis 2: miRs in transplanted MSC transfer to neighboring host cells or the extracellular environment via gap junctions and microvesicles (MVs). The proposed study represents the first in- depth attempt to elucidate the mechanism by which GATA-4 overexpression in MSC regulates expression of specific miRs that, in turn, enhance angiogenesis and cardioprotection when these MSC are transplanted into ischemic myocardium. The results of these studies should (i) provide evidence that MSC besides their differentiation potential serve as an important delivery vehicle for cardioprotectve proteins and molecules in repair of ischemic myocardium; (ii) explore the impact of transfer of specific molecules from MSC to the extracellular fluid space via MVs, and directly into CM via gap junctions or other intercellular channels. These findings may not only highlight the molecular mechanisms of MSCGATA-4 - mediated angiogenesis, but may also help formulate a novel therapeutic strategy for ischemia and offer insight into the progression of myocardial remodeling. PUBLIC HEALTH RELEVANCE: Coronary artery disease is the most common cause of heart infarction. The cell-based therapy is a putative treatment for end-stage heart failure to use stem cells for regeneration and as vehicle for transfer of cardioprotective and regenerative small noncoding RNA to the host damaged cells for repair.